US20050148551A1 - 7, 8 and 9-substituted tetracycline compounds - Google Patents

7, 8 and 9-substituted tetracycline compounds Download PDF

Info

Publication number
US20050148551A1
US20050148551A1 US10/866,220 US86622004A US2005148551A1 US 20050148551 A1 US20050148551 A1 US 20050148551A1 US 86622004 A US86622004 A US 86622004A US 2005148551 A1 US2005148551 A1 US 2005148551A1
Authority
US
United States
Prior art keywords
doxycycline
compound
phenyl
hydrogen
tetracycline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US10/866,220
Other versions
US7094806B2 (en
Inventor
Mark Nelson
Darrell Koza
Glen Rennie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tufts University
Original Assignee
Tufts University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/894,805 external-priority patent/US6624168B2/en
Priority to US10/866,220 priority Critical patent/US7094806B2/en
Application filed by Tufts University filed Critical Tufts University
Assigned to TUFTS COLLEGE, TRUSTEES OF reassignment TUFTS COLLEGE, TRUSTEES OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOZA, DARRELL J., RENNIE, GLEN, NELSON, MARK L.
Publication of US20050148551A1 publication Critical patent/US20050148551A1/en
Priority to US11/454,221 priority patent/US7361674B2/en
Publication of US7094806B2 publication Critical patent/US7094806B2/en
Application granted granted Critical
Priority to US12/074,466 priority patent/US7696188B2/en
Priority to US12/720,258 priority patent/US7875649B2/en
Priority to US13/012,590 priority patent/US8252777B2/en
Assigned to Mintz Levin Cohn Ferris Glovsky and Popeo PC reassignment Mintz Levin Cohn Ferris Glovsky and Popeo PC NOTICE Assignors: PARATEK PHARMACEUTICALS, INC.
Assigned to HBM HEALTHCARE INVESTMENTS (CAYMAN) LTD., AS COLLATERAL AGENT reassignment HBM HEALTHCARE INVESTMENTS (CAYMAN) LTD., AS COLLATERAL AGENT SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARATEK PHARMACEUTICALS, INC.
Assigned to PARATEK PHARMACEUTICALS, INC. reassignment PARATEK PHARMACEUTICALS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: HBM HEALTHCARE INVESTMENTS (CAYMAN) LTD., AS COLLATERAL AGENT
Assigned to PARATEK PHARMACEUTICALS, INC. reassignment PARATEK PHARMACEUTICALS, INC. TERMINATION OF LIEN ON PATENTS Assignors: Mintz Levin Cohn Ferris Glovsky and Popeo PC
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents

Definitions

  • New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Pat. Nos. 3,957,980; 3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889; 4,024,272; 4,126,680; 3,454,697; and 3,165,531. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
  • tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, including conjunctivitis, and psittacosis.
  • tetracyclines became known as “broad spectrum” antibiotics.
  • the tetracyclines as a class rapidly became widely used for therapeutic purposes.
  • the invention pertains, at least in part, to 7-, 8- or 9-substituted tetracycline compounds of the formula:
  • the tetracycline compound of the invention is a tetracycline derivative wherein R 5 is hydrogen, R 6 is methyl, R 6′ is hydroxyl, and R 7 is phenyl.
  • the tetracycline compound of the invention is a doxycycline derivative, wherein R 5 is hydroxyl, R 6 is methyl, and R 6′ is hydrogen.
  • the doxycycline derivative comprises R 7 groups such as lower alkenyl (e.g., ethenyl), lower alkynyl (e.g., ethynyl), heteroaryl (e.g., furanyl, dioxenyl, pyrazinyl, or pyridinyl), phenyl, halophenyl or phenylalkynyl.
  • Doxycycline derivatives also may comprise R 8 groups such as hydrogen, halogen (e.g., bromine), lower alkynyl (e.g., ethynyl), phenyl, or nitrophenyl.
  • R 7 is ethenyl or ethynyl; and R 8 and R 9 are each hydrogen.
  • R 7 is phenyl, halophenyl or phenylalkynyl; and R 8 and R 9 are each hydrogen.
  • R 7 is hydrogen, R 8 is halo, phenyl, or nitrophenyl
  • R 9 is hydrogen.
  • R 7 may be hydrogen, R 8 phenyl, and R 9 amino.
  • the tetracycline compound of the invention is a demeclocycline derivative, wherein R 5 is hydrogen, R 6 is hydroxyl, R 6′ is hydrogen, and R 7 is phenyl.
  • the tetracycline compound of the invention is aminocycline derivative wherein R 5 is hydroxyl, R 6 is hydrogen, R 6′ is hydrogen, R 7 is dimethylamino, and R 9 is lower alkynyl (e.g., ethynyl).
  • the invention also pertains to a method for treating a tetracycline responsive state in a mammal, by administering to a mammal a compound of formula I.
  • the invention relates to the use of a compound of formula I to treat a tetracycline responsive state.
  • the invention also pertains to pharmaceutical compositions comprising a compound of formula I, and to the use of a compound of formula I in the manufacture of a medicament to treat a tetracycline responsive state.
  • the invention pertains to, at least in part, to 7-, 8- or 9-substituted tetracycline compounds of the formula:
  • tetracycline compound includes compounds with a similar ring structure to tetracycline, such as those included in formula I.
  • Some examples of tetracycline compounds which can be modified include a substituent at position 7, 8 or 9 include tetracycline, demeclocycline, sancycline, and doxycycline; however, other derivatives and analogues comprising a similar ring structure are also included.
  • Table 1 depicts the structure of tetracycline, demeclocycline, sancycline, and doxycycline. TABLE I Tetracycline Demeclocycline Doxycycline Minocycline
  • the term “7, 8 or 9-substituted tetracycline compounds” includes tetracycline compounds with at least one substituent at the 7, 8 and/or 9 position, as described in formula I.
  • the substituted tetracycline compound is substituted tetracycline derivative (e.g., wherein R 4 and R 4′ are methyl, R 5 is hydrogen, R 6 is methyl and R 6′ is hydroxyl); substituted doxycycline derivative (e.g., wherein R 4 and R 4′ are methyl, R 5 is hydroxyl R 6 is methyl and R 6′ is hydrogen); substituted demeclocycline derivative (e.g., R 5 is hydrogen, R 6 is hydroxyl, R 6′ is hydrogen, R 7 is chloro and R 4 and R 4′ are each methyl); or substituted minocycline derivative (wherein R 4 and R 4′ are methyl; R 5 is hydrogen and R 6 and R 6′ are hydrogen atoms).
  • the substituted tetracycline compound of the invention is a tetracycline derivative, wherein R 5 is hydrogen, R 6 is methyl, R 6′ is hydroxyl, and R 7 is phenyl.
  • examples of such tetracycline compounds include 7-phenyl tetracycline.
  • the substituted tetracycline compound of the invention is a doxycycline derivative, wherein R 5 is hydroxyl, R 6 is methyl, and R 6′ is hydrogen.
  • doxycycline derivatives of tetracycline compounds of the invention include compounds wherein R 7 is hydrogen, R 8 is halo, phenyl, or nitrophenyl, and R 9 is hydrogen.
  • R 7 is hydrogen
  • R 8 is phenyl or lower alkynyl (e.g., ethynyl)
  • R 9 is amino.
  • R 7 and R 8 are both hydrogen and R 9 is acetamide.
  • the doxycycline derivatives include compounds wherein R 7 is lower alkenyl (e.g., ethenyl), lower alkynyl (e.g., ethynyl), phenyl, heteroaryl (e.g., furanyl, pyrazinyl, pyridinyl, or dioxenyl), acyl (e.g., lower alkyl carbonyl, e.g., methylcarbonyl), halophenyl or phenylalkynyl (e.g., phenylethynyl); and R 8 and R 9 are each hydrogen.
  • R 7 is lower alkenyl (e.g., ethenyl), lower alkynyl (e.g., ethynyl), phenyl, heteroaryl (e.g., furanyl, pyrazinyl, pyridinyl, or dioxenyl), acyl (e.g
  • Examples of such tetracycline compound which are doxycycline derivatives include 7-ethenyl doxycycline, 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, and 7-acyl doxycycline.
  • the tetracycline compound of the invention is a demeclocycline derivative, wherein R 5 is hydrogen, R 6 is hydroxyl, R 6′ is hydrogen, R 7 is phenyl, and R 8 and R 9 are both hydrogen.
  • demeclocycline derivatives include 7-phenyl demeclocycline.
  • the tetracycline compound of the invention is aminocycline derivative, wherein R 5 is hydroxyl, R 6 is hydrogen, R 6′ is hydrogen, R 7 is dimethylamino, R 8 is hydrogen, and R 9 is lower alkynyl (e.g., ethynyl). Examples include 9-ethynyl minocycline.
  • Compounds of the invention can be synthesized by transition metal catalyzed coupling of tetracyclines halogenated at the 7-, 8-, or 9-position.
  • transition metal catalysis many reactions between aryl halides and various reactive species have been developed using transition metal catalysis.
  • Coupling of aryl halides or triflates with main group organometallics with oxidate addition—transmetallation—reductive elimination reactions has been developed and occurs using a wide range of catalysts, such as Pd(Pd 3 ) 4 , Pd(dba) 2 , PdCl 2 , Pd(OAc) 2 , and PdCl 2 (CH 3 CN) 2 .
  • Ligands such as PPh 3 or AsPh 3 may be added to form catalysts in situ with palladium species such as Pd(dba) 2 or PdCl 2 .
  • copper salts such as CuCN or CuI may also be added to further enhance the reaction.
  • Scheme 1 An example of a coupling using a halogenated tetracycline compound is shown in Scheme 1.
  • X is bromine or iodine.
  • the substituted tetracycline compounds of the invention can be synthesized using organotin reagents, halogenated or triflate tetracycline compounds, and an appropriate catalyst (e.g., palladium).
  • organotin reagents include, for example, ethenyl tributyltin, ethynyl tributyltin, phenyl tributyltin, ethenyl trimethyl tin, ethynyl trimethyl tin, etc.
  • Stille type couplings are run by adding the transition metal (e.g., palladium) catalyst to a solution of the halogenated or triflate tetracycline compound and the organotin reagent in polar solvents.
  • transition metal e.g., palladium
  • Stille type couplings with alkynyl and alkenyl tin reagents are shown in Scheme 2, wherein X is a halogen or a triflate group.
  • 8-halogenated tetracycline compounds can be synthesized via azidotetracyclines.
  • the protonolysis of the aryl azides produces 8-halo-9-amino tetracycline in good yield.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which comprise oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 1 -C 6 includes alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • aryl includes groups with aromaticity, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms as well as multicyclic systems with at least one aromatic ring.
  • aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
  • heteroaryl refers to pyrazinyl, pyridinyl, furanyl, and dioxenyl groups.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulflhydryl, alkylthio, arylthio, thiocarboxylate
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • the term C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure, e.g., methyl, ethyl, propyl, butyl and pentyl.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms, e.g., ethenyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl, and pentynyl.
  • acyl includes compounds and moieties which contain the acyl radical (CH 3 CO—) or a carbonyl group.
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino,
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • amide or “aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy “alkenylaminocarboxy,” “alkynylaminocarboxy,” and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkylamino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkylamino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • dioxenyl refers to moieties of the formula:
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • halo includes, for example, substituents such as chlorine, fluorine, bromine, or iodine, as well as mono-, di- or tri-halgentated lower alkyl group, e.g., mono-, di- or tri-halogenated methyl groups.
  • substituents such as chlorine, fluorine, bromine, or iodine
  • mono-, di- or tri-halgentated lower alkyl group e.g., mono-, di- or tri-halogenated methyl groups.
  • the halo substitution of the phenyl substituent enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • hydroxy or “hydroxyl” includes groups with an —OH or —O ⁇ .
  • polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • Prodrugs are compounds which are converted in vivo to active forms (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action”, Academic Press, Chp. 8). Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound. For example, a hydroxyl group, can be esterified, e.g., with a carboxylic acid group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
  • prodrug moiety includes moieties which can be metabolized in vivo to a hydroxyl group and moieties which may advantageously remain esterified in vivo.
  • the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups.
  • Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides,
  • the invention also features a method for treating a tetracycline compound responsive state in a subject, by administering to the subject a 7-, 8-, or 9-substituted tetracycline compound of the invention, e.g., a compound of formula I. Preferably, an effective amount of the tetracycline compound is administered.
  • Examples of 7, 8 or 9-substituted tetracycline compounds of the invention include 7-phenyl tetracycline, 7-ethenyl doxycycline 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-phenyl demeclocycline, and 9-ethynyl minocycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyr
  • tetracycline compound responsive state includes states which can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the invention.
  • Tetracycline compound responsive states include bacterial infections (including those which are resistant to other tetracycline compounds), cancer, diabetes, and other states for which tetracycline compounds have been found to be active (see, for example, U.S. Pat. Nos. 5,789,395; 5,834,450; and 5,532,227, incorporated herein by reference).
  • Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infection, mastitis and the like.
  • methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al., Cancer Res., 48: 6686-6690 (1988)).
  • Bacterial infections may be caused by a wide variety of gram positive and gram negative bacteria.
  • the compounds of the invention are useful as antibiotics against organisms which are resistant to other tetracycline compounds.
  • the antibiotic activity of the tetracycline compounds of the invention may be determined using the method discussed in Example 2, or by using the in vitro standard broth dilution method described in Waitz, J. A., National Commission for Clinical Laboratory Standards, Document M 7- A 2, vol. 10, no. 8, pp. 13-20, 2 nd edition, Villanova, Pa. (1990).
  • the tetracycline compounds may also be used to treat infections traditionally treated with tetracycline compounds such as, for example, rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, psittacosis.
  • the tetracycline compounds may be used to treat infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus or E. faecalis .
  • the tetracycline compound is used to treat a bacterial infection that is resistant to other tetracycline antibiotic compounds.
  • the tetracycline compound of the invention may be administered with a pharmaceutically acceptable carrier.
  • the language “effective amount” of the compound is that amount necessary or sufficient to treat or prevent a tetracycline compound responsive state.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular tetracycline compound. For example, the choice of the tetracycline compound can affect what constitutes an “effective amount”.
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the tetracycline compound without undue experimentation.
  • the invention also pertains to methods of treatment against microorganism infections and associated diseases.
  • the methods include administration of an effective amount of one or more tetracycline compounds to a subject.
  • the subject can be either a plant or, advantageously, an animal, e.g., a mammal, e.g., a human.
  • one or more tetracycline compounds of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • the pharmaceutical composition comprises a 7-, 8 or 9-substituted tetracycline compound of the invention, e.g., of formula I.
  • the 7, 8 or 9-substituted tetracycline compound is 7-phenyl tetracycline, 7-ethenyl doxycycline 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-phenyl demeclocycline, and 9-ethynyl
  • pharmaceutically acceptable carrier includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g., treat or prevent a tetracycline compound responsive state.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • the tetracycline compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of the tetracycline compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate; benzenesulfonate
  • salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • the tetracycline compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those tetracycline compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the pharmaceutically acceptable base addition salts of tetracycline compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods.
  • these salts may be readily prepared by treating the tetracycline compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure.
  • a lower alkyl alcohol solution of the tetracycline compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.
  • tetracycline compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes.
  • these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • compositions of the invention may be administered alone or in combination with other known compositions for treating tetracycline responsive states in a mammal.
  • Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas).
  • the language “in combination with” a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the therapeutically composition known in the art for treating tetracycline responsive states can be used in the methods of the invention.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables.
  • topical administration examples include transdermal, buccal or sublingual application.
  • therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream.
  • topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
  • topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like.
  • materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
  • tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats.
  • livestock such as cattle, sheep, goats, cows, swine and the like
  • poultry such as chickens, ducks, geese, turkeys and the like
  • horses such as dogs and cats.
  • the compounds of the invention may be used to treat non-animal subjects, such as plants.
  • compounds of the invention for treatment can be administered to a subject in dosages used in prior tetracycline therapies. See, for example, the Physicians' Desk Reference .
  • a suitable effective dose of one or more compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of body weight of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • the invention also pertains to the use of a tetracycline compound of formula I, for the preparation of a medicament.
  • the medicament may include a pharmaceutically acceptable carrier and the tetracycline compound is an effective amount, e.g., an effective amount to treat a tetracycline responsive state.
  • the invention also pertains to the use of a tetracycline compound of formula I to treat a tetracycline responsive state, e.g., in a subject, e.g., a mammal, e.g., a human.
  • N-iodosuccinimide N-iodosuccinimide
  • the reaction proceeded for 5 hours before being removed from the ice bath.
  • the reaction mixture was then analyzed by HPLC and TLC, showed the product of D-ring iodotetracyclines.
  • the sulfuric acid was dripped slowly 1 L of ice water and extracted 7 times with 300 mL of n-butanol. The solvent was removed in vacuo to produce a mixture of three products.
  • the 7-iodo regioisomer, 9-regioisomer and 7,9-diiodo tetracycline compound derivatives were purified by preparative HPLC chromatography and by methods known in the art.
  • 9-NO 2 doxycycline (1 g) was dissolved in methanol (50 ml) and poured into a Parr apparatus with 100 mg of 10% Pd/C. The reaction was charged with H 2 and shaken for 2 hours. The 9-amino doxycycline was separated by preparative apic purification to produce 9-NH 2 doxycycline and 7-NH 2 doxycycline in a 7:2 ratio.
  • 9-NH 2 doxycycline (1.5 g) was dissolved in 50 ml of 0.1N methanol HCl and 2.2 ml of butyl nitrate was subsequently added. The reaction was stirred for 1 hour, then the product was precipitated in 400 mL of dry ether to produce the 9-diazonium salt of doxycycline.
  • the final cell density should be approximately 5 ⁇ 10 5 CFU/ml.
  • These plates are incubated at 35° C. in an ambient air incubator for approximately 18 hr. The plates are read with a microplate reader and are visually inspected when necessary.
  • the MIC is defined as the lowest concentration of the tetracycline compound that inhibits growth.

Abstract

7, 8 and 9-substituted tetracycline compounds, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7, 8 and 9-substituted tetracycline compounds are described.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 10/652,713, filed on Aug. 28, 2003, which is a continuation of U.S. patent application Ser. No. 09/894,805, filed on Jun. 29, 2001 (U.S. Pat. No. 6,624,168), which claims priority to U.S. Provisional Patent Application Ser. No. 60/216,656, entitled “7, 8 and 9-Substituted Tetracycline Compounds,” filed on Jul. 7, 2000. The application is related to International Patent Application Serial No. PCT/US00/21366, entitled, “8-Substituted Tetracycline Compounds,” filed on Aug. 4, 2000. The entire contents of all the aforementioned patent applications are hereby incorporated herein by reference.
  • BACKGROUND OF THE INVENTION
  • The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bactericidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of tetracycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972.
  • Recently, research efforts have focused on developing new tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Pat. Nos. 3,957,980; 3,674,859; 2,980,584; 2,990,331; 3,062,717; 3,557,280; 4,018,889; 4,024,272; 4,126,680; 3,454,697; and 3,165,531. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
  • Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, including conjunctivitis, and psittacosis. Hence, tetracyclines became known as “broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice.
  • SUMMARY OF THE INVENTION
  • The invention pertains, at least in part, to 7-, 8- or 9-substituted tetracycline compounds of the formula:
    Figure US20050148551A1-20050707-C00001
      • wherein:
        • R4 and R4′ are each methyl;
        • R5 is hydrogen or hydroxyl;
        • R6 and R6′ are each independently hydrogen, methyl, or hydroxyl;
        • R7 is hydrogen, lower alkenyl, lower alkynyl, phenyl, halophenyl, acyl, heteroaryl, phenylalkynyl, or dimethylamino; and
        • R8 is hydrogen, phenyl, nitrophenyl, halo, or lower alkynyl; and
        • R9 is hydrogen, amino, acetamide, or lower alkynyl; and provided that at least one of R7, R8, or R9 is not hydrogen; and pharmaceutically acceptable salts thereof.
  • In an embodiment, the tetracycline compound of the invention is a tetracycline derivative wherein R5 is hydrogen, R6 is methyl, R6′ is hydroxyl, and R7 is phenyl.
  • In another embodiment, the tetracycline compound of the invention is a doxycycline derivative, wherein R5 is hydroxyl, R6 is methyl, and R6′ is hydrogen. In a further embodiment, the doxycycline derivative comprises R7 groups such as lower alkenyl (e.g., ethenyl), lower alkynyl (e.g., ethynyl), heteroaryl (e.g., furanyl, dioxenyl, pyrazinyl, or pyridinyl), phenyl, halophenyl or phenylalkynyl. Doxycycline derivatives also may comprise R8 groups such as hydrogen, halogen (e.g., bromine), lower alkynyl (e.g., ethynyl), phenyl, or nitrophenyl. In certain embodiments, R7 is ethenyl or ethynyl; and R8 and R9 are each hydrogen. In another, R7 is phenyl, halophenyl or phenylalkynyl; and R8 and R9 are each hydrogen. Alternatively, R7 is hydrogen, R8 is halo, phenyl, or nitrophenyl, and R9 is hydrogen. Further, R7 may be hydrogen, R8 phenyl, and R9 amino.
  • In another embodiment, the tetracycline compound of the invention is a demeclocycline derivative, wherein R5 is hydrogen, R6 is hydroxyl, R6′ is hydrogen, and R7 is phenyl. In another embodiment, the tetracycline compound of the invention is aminocycline derivative wherein R5 is hydroxyl, R6 is hydrogen, R6′ is hydrogen, R7 is dimethylamino, and R9 is lower alkynyl (e.g., ethynyl).
  • The invention also pertains to a method for treating a tetracycline responsive state in a mammal, by administering to a mammal a compound of formula I. In another aspect, the invention relates to the use of a compound of formula I to treat a tetracycline responsive state. The invention also pertains to pharmaceutical compositions comprising a compound of formula I, and to the use of a compound of formula I in the manufacture of a medicament to treat a tetracycline responsive state.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The invention pertains to, at least in part, to 7-, 8- or 9-substituted tetracycline compounds of the formula:
    Figure US20050148551A1-20050707-C00002
      • wherein:
        • R4 and R4′ are each methyl;
        • R5 is hydrogen or hydroxyl;
        • R6 and R6′ are each independently hydrogen, methyl, or hydroxyl;
        • R7 is hydrogen, lower alkenyl, lower alkynyl, phenyl, halophenyl, acyl, phenylalkynyl, heteroaryl, or dimethylamino; and
        • R8 is hydrogen, phenyl, nitrophenyl, halo, or lower alkynyl;
        • and R9 is hydrogen, amino, acetamide, or lower alkynyl; and provided that at least one of R7, R8, or R9 is not hydrogen; and pharmaceutically acceptable salts thereof.
  • The term “tetracycline compound” includes compounds with a similar ring structure to tetracycline, such as those included in formula I. Some examples of tetracycline compounds which can be modified include a substituent at position 7, 8 or 9 include tetracycline, demeclocycline, sancycline, and doxycycline; however, other derivatives and analogues comprising a similar ring structure are also included. Table 1 depicts the structure of tetracycline, demeclocycline, sancycline, and doxycycline.
    TABLE I
    Figure US20050148551A1-20050707-C00003
    Tetracycline
    Figure US20050148551A1-20050707-C00004
    Demeclocycline
    Figure US20050148551A1-20050707-C00005
    Doxycycline
    Figure US20050148551A1-20050707-C00006
    Minocycline
  • The term “7, 8 or 9-substituted tetracycline compounds” includes tetracycline compounds with at least one substituent at the 7, 8 and/or 9 position, as described in formula I. In an embodiment, the substituted tetracycline compound is substituted tetracycline derivative (e.g., wherein R4 and R4′ are methyl, R5 is hydrogen, R6 is methyl and R6′ is hydroxyl); substituted doxycycline derivative (e.g., wherein R4 and R4′ are methyl, R5 is hydroxyl R6 is methyl and R6′ is hydrogen); substituted demeclocycline derivative (e.g., R5 is hydrogen, R6 is hydroxyl, R6′ is hydrogen, R7 is chloro and R4 and R4′ are each methyl); or substituted minocycline derivative (wherein R4 and R4′ are methyl; R5 is hydrogen and R6 and R6′ are hydrogen atoms).
  • In an embodiment, the substituted tetracycline compound of the invention is a tetracycline derivative, wherein R5 is hydrogen, R6 is methyl, R6′ is hydroxyl, and R7 is phenyl. Examples of such tetracycline compounds include 7-phenyl tetracycline.
  • In another embodiment, the substituted tetracycline compound of the invention is a doxycycline derivative, wherein R5 is hydroxyl, R6 is methyl, and R6′ is hydrogen.
  • In an alternate embodiment, doxycycline derivatives of tetracycline compounds of the invention include compounds wherein R7 is hydrogen, R8 is halo, phenyl, or nitrophenyl, and R9 is hydrogen. In another alternate embodiment, R7 is hydrogen, R8 is phenyl or lower alkynyl (e.g., ethynyl), and R9 is amino. In yet another alternate embodiment, R7 and R8 are both hydrogen and R9 is acetamide.
  • In further embodiments of the invention, the doxycycline derivatives include compounds wherein R7 is lower alkenyl (e.g., ethenyl), lower alkynyl (e.g., ethynyl), phenyl, heteroaryl (e.g., furanyl, pyrazinyl, pyridinyl, or dioxenyl), acyl (e.g., lower alkyl carbonyl, e.g., methylcarbonyl), halophenyl or phenylalkynyl (e.g., phenylethynyl); and R8 and R9 are each hydrogen.
  • Examples of such tetracycline compound which are doxycycline derivatives include 7-ethenyl doxycycline, 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, and 7-acyl doxycycline.
  • In another embodiment, the tetracycline compound of the invention is a demeclocycline derivative, wherein R5 is hydrogen, R6 is hydroxyl, R6′ is hydrogen, R7 is phenyl, and R8 and R9 are both hydrogen. Examples of demeclocycline derivatives include 7-phenyl demeclocycline.
  • In another embodiment, the tetracycline compound of the invention is aminocycline derivative, wherein R5 is hydroxyl, R6 is hydrogen, R6′ is hydrogen, R7 is dimethylamino, R8 is hydrogen, and R9 is lower alkynyl (e.g., ethynyl). Examples include 9-ethynyl minocycline.
  • Compounds of the invention can be synthesized by transition metal catalyzed coupling of tetracyclines halogenated at the 7-, 8-, or 9-position. For example, many reactions between aryl halides and various reactive species have been developed using transition metal catalysis. Coupling of aryl halides or triflates with main group organometallics with oxidate addition—transmetallation—reductive elimination reactions has been developed and occurs using a wide range of catalysts, such as Pd(Pd3)4, Pd(dba)2, PdCl2, Pd(OAc)2, and PdCl2(CH3CN)2. Ligands such as PPh3 or AsPh3 may be added to form catalysts in situ with palladium species such as Pd(dba)2 or PdCl2. Furthermore, copper salts, such as CuCN or CuI may also be added to further enhance the reaction. An example of a coupling using a halogenated tetracycline compound is shown in Scheme 1. In Scheme 1, X is bromine or iodine.
    Figure US20050148551A1-20050707-C00007
  • The substituted tetracycline compounds of the invention can be synthesized using organotin reagents, halogenated or triflate tetracycline compounds, and an appropriate catalyst (e.g., palladium). Examples of tin reagents include, for example, ethenyl tributyltin, ethynyl tributyltin, phenyl tributyltin, ethenyl trimethyl tin, ethynyl trimethyl tin, etc. These Stille type couplings are run by adding the transition metal (e.g., palladium) catalyst to a solution of the halogenated or triflate tetracycline compound and the organotin reagent in polar solvents. Stille type couplings with alkynyl and alkenyl tin reagents are shown in Scheme 2, wherein X is a halogen or a triflate group.
    Figure US20050148551A1-20050707-C00008
  • Other methods of synthesizing the 7-, 8-, and 9-substituted tetracycline compounds of the invention include coupling halogenated tetracycline compounds to boronic acids using Suzuki type couplings (M. J. Sharp et al. Tetrahedron Lett. 28 (1987) 5093; W. Cheng, et al. Tetrahedron Lett. 28 (1987) 5097; Alves, A. B. et al. Tetrahedron Lett. 29 (1988) 2135; D. Muller, et al. Tetrahedron Lett. 32 (1991) 2135), Grignard reagents (K. Tamao et al. Bull. Chem. Soc. Jpn. 49 (1976) 1958), or organolithium reagents (S.-I. Murahashi et al., J. Org. Chem 44 (1979) 2408) and a transition metal catalyst, as shown in Scheme 3.
    Figure US20050148551A1-20050707-C00009
  • 8-halogenated tetracycline compounds can be synthesized via azidotetracyclines. The protonolysis of the aryl azides produces 8-halo-9-amino tetracycline in good yield.
  • The term “alkyl” includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which comprise oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C1-C6 includes alkyl groups containing 1 to 6 carbon atoms.
  • Moreover, the term alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • The term “aryl” includes groups with aromaticity, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms as well as multicyclic systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl). In a further embodiment, the term “heteroaryl” refers to pyrazinyl, pyridinyl, furanyl, and dioxenyl groups.
  • The term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • For example, the term “alkenyl” includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C2-C6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • Moreover, the term alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulflhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In a further embodiment, the term “lower alkenyl” refers to moieties with 2-5 carbons. Advantageous lower alkenyl groups include ethenyl groups.
  • The term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • For example, the term “alkynyl” includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term C2-C6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • Moreover, the term alkynyl includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure, e.g., methyl, ethyl, propyl, butyl and pentyl. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms, e.g., ethenyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl, and pentynyl.
  • The term “acyl” includes compounds and moieties which contain the acyl radical (CH3CO—) or a carbonyl group. The term “substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • The term “acylamino” includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • The term “aroyl” includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
  • The term “amide” or “aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes “alkaminocarboxy” groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • The term “amine” or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term “alkylamino” includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term “dialkylamino” includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term “arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term “alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • The term “carbonyl” or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • The term “dioxenyl” refers to moieties of the formula:
    Figure US20050148551A1-20050707-C00010
  • The term “ester” includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above.
  • The term “ether” includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes “alkoxyalkyl” which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • The term “halo” includes, for example, substituents such as chlorine, fluorine, bromine, or iodine, as well as mono-, di- or tri-halgentated lower alkyl group, e.g., mono-, di- or tri-halogenated methyl groups. In certain embodiments, the halo substitution of the phenyl substituent enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • The term “heteroatom” includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O.
  • The terms “polycyclyl” or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • The term “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • The term “thioether” includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” and alkthioalkynyls” refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • Prodrugs are compounds which are converted in vivo to active forms (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action”, Academic Press, Chp. 8). Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound. For example, a hydroxyl group, can be esterified, e.g., with a carboxylic acid group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
  • The term “prodrug moiety” includes moieties which can be metabolized in vivo to a hydroxyl group and moieties which may advantageously remain esterified in vivo. Preferably, the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters.
  • The invention also features a method for treating a tetracycline compound responsive state in a subject, by administering to the subject a 7-, 8-, or 9-substituted tetracycline compound of the invention, e.g., a compound of formula I. Preferably, an effective amount of the tetracycline compound is administered. Examples of 7, 8 or 9-substituted tetracycline compounds of the invention include 7-phenyl tetracycline, 7-ethenyl doxycycline 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-phenyl demeclocycline, and 9-ethynyl minocycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, and 7-acetyl doxycycline.
  • The language “tetracycline compound responsive state” includes states which can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the invention. Tetracycline compound responsive states include bacterial infections (including those which are resistant to other tetracycline compounds), cancer, diabetes, and other states for which tetracycline compounds have been found to be active (see, for example, U.S. Pat. Nos. 5,789,395; 5,834,450; and 5,532,227, incorporated herein by reference). Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infection, mastitis and the like. In addition, methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al., Cancer Res., 48: 6686-6690 (1988)).
  • Bacterial infections may be caused by a wide variety of gram positive and gram negative bacteria. The compounds of the invention are useful as antibiotics against organisms which are resistant to other tetracycline compounds. The antibiotic activity of the tetracycline compounds of the invention may be determined using the method discussed in Example 2, or by using the in vitro standard broth dilution method described in Waitz, J. A., National Commission for Clinical Laboratory Standards, Document M7-A2, vol. 10, no. 8, pp. 13-20, 2nd edition, Villanova, Pa. (1990).
  • The tetracycline compounds may also be used to treat infections traditionally treated with tetracycline compounds such as, for example, rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, psittacosis. The tetracycline compounds may be used to treat infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus or E. faecalis. In one embodiment, the tetracycline compound is used to treat a bacterial infection that is resistant to other tetracycline antibiotic compounds. The tetracycline compound of the invention may be administered with a pharmaceutically acceptable carrier.
  • The language “effective amount” of the compound is that amount necessary or sufficient to treat or prevent a tetracycline compound responsive state. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular tetracycline compound. For example, the choice of the tetracycline compound can affect what constitutes an “effective amount”. One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the tetracycline compound without undue experimentation.
  • The invention also pertains to methods of treatment against microorganism infections and associated diseases. The methods include administration of an effective amount of one or more tetracycline compounds to a subject. The subject can be either a plant or, advantageously, an animal, e.g., a mammal, e.g., a human.
  • In the therapeutic methods of the invention, one or more tetracycline compounds of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • In one embodiment, the pharmaceutical composition comprises a 7-, 8 or 9-substituted tetracycline compound of the invention, e.g., of formula I. In a further embodiment, the 7, 8 or 9-substituted tetracycline compound is 7-phenyl tetracycline, 7-ethenyl doxycycline 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-phenyl demeclocycline, and 9-ethynyl minocycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, or 7-acetyl doxycycline.
  • The language “pharmaceutically acceptable carrier” includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g., treat or prevent a tetracycline compound responsive state. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • The tetracycline compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of the tetracycline compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate; benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal, it is often desirable in practice to initially isolate a tetracycline compound of the invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • The preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • The tetracycline compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those tetracycline compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. The pharmaceutically acceptable base addition salts of tetracycline compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods. Thus, these salts may be readily prepared by treating the tetracycline compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the tetracycline compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.
  • The preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • The tetracycline compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • The pharmaceutical compositions of the invention may be administered alone or in combination with other known compositions for treating tetracycline responsive states in a mammal. Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas). The language “in combination with” a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the therapeutically composition known in the art for treating tetracycline responsive states can be used in the methods of the invention.
  • The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses. For example, the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For parenteral application, examples of suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables.
  • Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin. Examples of methods of topical administration include transdermal, buccal or sublingual application. For topical applications, therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream. Such topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils. Other possible topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like. In addition, materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
  • For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • In addition to treatment of human subjects, the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats. Also, the compounds of the invention may be used to treat non-animal subjects, such as plants.
  • It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines.
  • In general, compounds of the invention for treatment can be administered to a subject in dosages used in prior tetracycline therapies. See, for example, the Physicians' Desk Reference. For example, a suitable effective dose of one or more compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of body weight of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day. The desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • It will also be understood that normal, conventionally known precautions will be taken regarding the administration of tetracyclines generally to ensure their efficacy under normal use circumstances. Especially when employed for therapeutic treatment of humans and animals in vivo, the practitioner should take all sensible precautions to avoid conventionally known contradictions and toxic effects. Thus, the conventionally recognized adverse reactions of gastrointestinal distress and inflammations, the renal toxicity, hypersensitivity reactions, changes in blood, and impairment of absorption through aluminum, calcium, and magnesium ions should be duly considered in the conventional manner.
  • Furthermore, the invention also pertains to the use of a tetracycline compound of formula I, for the preparation of a medicament. The medicament may include a pharmaceutically acceptable carrier and the tetracycline compound is an effective amount, e.g., an effective amount to treat a tetracycline responsive state.
  • In yet another embodiment, the invention also pertains to the use of a tetracycline compound of formula I to treat a tetracycline responsive state, e.g., in a subject, e.g., a mammal, e.g., a human.
  • Compounds of the invention may be made as described below, with modifications to the procedure below within the skill of those of ordinary skill in the art.
  • EXAMPLE 1 Synthesis of 7-, 8- and 9-Substituted Tetracycline Compounds
  • 7- and 9-Iodo Tetracycline Compounds
  • Five grams of a tetracycline compound was dissolved in 85 mL of concentrated sulfuric acid that was cooled to 0° C. (on ice). N-iodosuccinimide (NIS) was added to the reaction in 300 mg portions every 15 minutes. The reaction proceded for 5 hours before being removed from the ice bath. The reaction mixture was then analyzed by HPLC and TLC, showed the product of D-ring iodotetracyclines. After the reaction was complete, the sulfuric acid was dripped slowly 1 L of ice water and extracted 7 times with 300 mL of n-butanol. The solvent was removed in vacuo to produce a mixture of three products. The 7-iodo regioisomer, 9-regioisomer and 7,9-diiodo tetracycline compound derivatives were purified by preparative HPLC chromatography and by methods known in the art.
  • 9-NO2 Doxycycline
  • 1.0 g of doxycycline HCl was dissolved in concentrated H2SO4 (5 ml) and NaNO3 (1.1 eq) was added over 1 minute. The reaction was stirred for 1 hour and subsequently dripped into cold, rapidly stirred ether (500 ml). The precipitate was washed with ether and dried in vacuum to yield 9-NO2 doxycycline without further purification.
  • 9-NH2 Doxycycline:
  • 9-NO2 doxycycline (1 g) was dissolved in methanol (50 ml) and poured into a Parr apparatus with 100 mg of 10% Pd/C. The reaction was charged with H2 and shaken for 2 hours. The 9-amino doxycycline was separated by preparative apic purification to produce 9-NH2 doxycycline and 7-NH2 doxycycline in a 7:2 ratio.
  • 9-N2 Doxycycline
  • 9-NH2 doxycycline (1.5 g) was dissolved in 50 ml of 0.1N methanol HCl and 2.2 ml of butyl nitrate was subsequently added. The reaction was stirred for 1 hour, then the product was precipitated in 400 mL of dry ether to produce the 9-diazonium salt of doxycycline.
  • 9-Azido Doxycycline
  • Sodium azide (0.126 g) was added to a warm 0.1 N methanol/HCl solution of the 9-diazonium salt (1 g). The mixture was then stirred at room temperature for 4 hours and the product was obtained by precipitation into diethyl ether. The solid was collected to yield 87% of the desired product (9-azido doxycycline).
  • 9-NH2-8-Bromo Doxycycline
  • 0.5 g of 9-azido doxycycline was added to 10 mL of HBr in acetic acid (30 wt %) and the reaction was stirred at room temperature for 1 hour. The product was obtained as a yellow powder in 56% yield by preparative C18 HPLC.
  • 8-Bromo Doxycycline
  • 100 mg of 9-amino-8-bromo doxycycline was reacted with 1.1 g of butyl nitrate in 0.1N HCl to produce the 9-diazonium salt of the 8-bromo doxycycline. The reaction was treated with phosphoric acid to yield the product as crude solid. Preparative HPLC produced the product as a yellow solid in 64% yield.
  • 7-Phenyl Tetracycline
  • 7-iodotetracycline (0.37 mmol), 30 mg Pd(PPh3)2Cl2, 10 mg AsPh3, and 6 mg of CuI was dissolved in 25 ml of toluene with stirring. Phenyl tri-n-butyltin (0.050 mL) was added and the solution was refluxed for 6 hours under nitrogen. The solution was then cooled to room temperature, filtered, the solvent removed and the crude residue purified by preparative thin layer chromatography.
  • EXAMPLE 2 In Vitro Minimum Inhibitory Concentration (MIC) Assay
  • The following assay is used to determine the efficacy of tetracycline compounds against common bacteria. 2 mg of each compound is dissolved in 100 μl of DMSO. The solution is then added to cation-adjusted Mueller Hinton broth (CAMHB), which results in a final compound concentration of 200 μg per ml. The tetracycline compound solutions are diluted to 50 μL volumes, with a test compound concentration of 0.098 μg/ml. Optical density (OD) determinations are made from fresh log-phase broth cultures of the test strains. Dilutions are made to achieve a final cell density of 1×106 CFU/ml. At OD=1, cell densities for different genera should be approximately:
    E. coli 1 × 109 CFU/ml
    S. aureus 5 × 108 CFU/ml
    Enterococcus sp. 2.5 × 109 CFU/ml
  • 50 μl of the cell suspensions are added to each well of microtiter plates. The final cell density should be approximately 5×105 CFU/ml. These plates are incubated at 35° C. in an ambient air incubator for approximately 18 hr. The plates are read with a microplate reader and are visually inspected when necessary. The MIC is defined as the lowest concentration of the tetracycline compound that inhibits growth.
  • Equivalents
  • Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the present invention and embodiments thereof.

Claims (26)

1. A 7-, 8- or 9-substituted tetracycline compound of the formula:
Figure US20050148551A1-20050707-C00011
wherein:
R4 and R4′ are each methyl;
R5 is hydrogen or hydroxyl;
R6 and R6′ are each independently hydrogen, methyl, or hydroxyl;
R7 is hydrogen, lower alkenyl, lower alkynyl, phenyl, halophenyl, acyl, phenylalkynyl, heteroaryl, or dimethylamino; and
R8 is hydrogen, phenyl, nitrophenyl, halo, or lower alkynyl;
and R9 is hydrogen, amino, acetamide, or lower alkynyl; and provided that at least one of R7, R8, or R9 is not hydrogen; and pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein R5 is hydrogen, R6 is methyl, R6′ is hydroxyl, R7 is phenyl, and R8 and R9 are each hydrogen.
3. The compound of claim 1, wherein R5 is hydroxyl, R6 is methyl, and R6′ is hydrogen.
4. The compound of claim 3, wherein R7 is ethenyl, ethynyl, phenyl, halophenyl, acyl, phenylethynyl, furanyl, dioxenyl, pyrazinyl, or pyridinyl, and R8 and R9 are each hydrogen.
5. The compound of claim 4, wherein said compound is 7-ethenyl doxycycline or 7-ethynyl doxycycline.
6. The compound of claim 3, wherein said compound is 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, or 7-acyl doxycycline.
7. The compound of claim 4, wherein R7 is phenyl, acyl, fluorophenyl or phenylethynyl.
8. The compound of claim 6, wherein said compound is 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-acyl doxycycline or 7-phenylethynyl doxycycline.
9. The compound of claim 3, wherein R8 is phenyl, bromo, or nitrophenyl; and R7 and R9 are hydrogen.
10. The compound of claim 9, wherein said compound is 8-phenyl doxycycline, 8-bromo doxycycline or 8-(p-nitrophenyl) doxycycline.
11. The compound of claim 3, wherein R8 is phenyl or ethynyl, and R9 is amino.
12. The compound of claim 11, wherein said compound is 8-ethynyl-9-amino doxycycline or 8-phenyl-9-amino doxycycline.
13. The compound of claim 3, wherein R9 is acetamide, and R7 and R8 are each hydrogen.
14. The compound of claim 1, wherein R5 is hydrogen, R6 is hydroxyl, R6′ is hydrogen, and R7 is phenyl.
15. The compound of claim 1, wherein R5 is hydroxyl, R6 is hydrogen, R6′ is hydrogen, R7 is dimethylamino, R8 is hydrogen and R9 is ethynyl.
16. The compound of claim 15, wherein said compound is 9-ethynyl minocycline.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17, wherein said compound is selected from the group consisting of 7-phenyl demeclocycline, 7-phenyl tetracycline, 7-(2-pyridinyl) doxycycline, 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-acyl doxycycline, 7-(2-furanyl) doxycycline, 7-phenylethynyl doxycycline, 7-(1,4-dioxenyl) doxycycline, 7-ethenyl doxycycline, 9-acetamide doxycycline, 8-phenyl-9-amino doxycycline, 9-ethynyl minocycline, 8-bromo doxycycline, 8-phenyl doxycycline, 8-(p-nitrophenyl) doxycycline and 8-ethynyl-9-amino doxycycline.
19. A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a 7, 8 or 9-substituted tetracycline compound of claim 1.
20. The method of claim 19 wherein said compound is selected from the group consisting of 7-phenyl tetracycline, 7-ethenyl doxycycline 7-ethynyl doxycycline, 7-phenyl doxycycline, 7-(4-fluorophenyl) doxycycline, 7-phenylethynyl doxycycline, 9-acetamide doxycycline, 8-phenyl doxycycline, 8-bromo doxycycline, 8-(p-nitrophenyl) doxycycline, 8-ethynyl-9-amino doxycycline, 8-phenyl-9-amino doxycycline, 7-phenyl demeclocycline, 9-ethynyl minocycline, 7-(1,4-dioxenyl) doxycycline, 7-(2-furanyl) doxycycline, 7-(2-pyrazinyl) doxycycline, 7-(2-pyridinyl) doxycycline, or 7-acyl doxycycline.
21. The method of claim 19, wherein said tetracycline responsive state is a bacterial infection.
22. The method of claim 21, wherein said bacterial infection is associated with E. coli.
23. The method of claim 21, wherein said bacterial infection is associated with S. aureus.
24. The method of claim 21, wherein said bacterial infection is associated with E. faecalis.
25. The method of claim 21, wherein said bacterial infection is resistant to other tetracycline antibiotics.
26. The method of claim 19, wherein said compound is administered with a pharmaceutically acceptable carrier.
US10/866,220 2000-07-07 2004-06-10 7, 8 and 9-substituted tetracycline compounds Expired - Fee Related US7094806B2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US10/866,220 US7094806B2 (en) 2000-07-07 2004-06-10 7, 8 and 9-substituted tetracycline compounds
US11/454,221 US7361674B2 (en) 2000-07-07 2006-06-16 7, 8 and 9-substituted tetracycline compounds
US12/074,466 US7696188B2 (en) 2000-07-07 2008-03-04 7,8 and 9-substituted tetracycline compounds
US12/720,258 US7875649B2 (en) 2000-07-07 2010-03-09 7, 8 and 9-substituted tetracycline compounds
US13/012,590 US8252777B2 (en) 2000-07-07 2011-01-24 7, 8 and 9-substituted tetracycline compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US21665600P 2000-07-07 2000-07-07
US09/894,805 US6624168B2 (en) 2000-07-07 2001-06-29 7,8 and 9-substituted tetracycline compounds
US65271303A 2003-08-28 2003-08-28
US10/866,220 US7094806B2 (en) 2000-07-07 2004-06-10 7, 8 and 9-substituted tetracycline compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US65271303A Continuation 2000-07-07 2003-08-28

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/454,221 Continuation US7361674B2 (en) 2000-07-07 2006-06-16 7, 8 and 9-substituted tetracycline compounds

Publications (2)

Publication Number Publication Date
US20050148551A1 true US20050148551A1 (en) 2005-07-07
US7094806B2 US7094806B2 (en) 2006-08-22

Family

ID=46302163

Family Applications (5)

Application Number Title Priority Date Filing Date
US10/866,220 Expired - Fee Related US7094806B2 (en) 2000-07-07 2004-06-10 7, 8 and 9-substituted tetracycline compounds
US11/454,221 Expired - Lifetime US7361674B2 (en) 2000-07-07 2006-06-16 7, 8 and 9-substituted tetracycline compounds
US12/074,466 Expired - Fee Related US7696188B2 (en) 2000-07-07 2008-03-04 7,8 and 9-substituted tetracycline compounds
US12/720,258 Expired - Fee Related US7875649B2 (en) 2000-07-07 2010-03-09 7, 8 and 9-substituted tetracycline compounds
US13/012,590 Expired - Lifetime US8252777B2 (en) 2000-07-07 2011-01-24 7, 8 and 9-substituted tetracycline compounds

Family Applications After (4)

Application Number Title Priority Date Filing Date
US11/454,221 Expired - Lifetime US7361674B2 (en) 2000-07-07 2006-06-16 7, 8 and 9-substituted tetracycline compounds
US12/074,466 Expired - Fee Related US7696188B2 (en) 2000-07-07 2008-03-04 7,8 and 9-substituted tetracycline compounds
US12/720,258 Expired - Fee Related US7875649B2 (en) 2000-07-07 2010-03-09 7, 8 and 9-substituted tetracycline compounds
US13/012,590 Expired - Lifetime US8252777B2 (en) 2000-07-07 2011-01-24 7, 8 and 9-substituted tetracycline compounds

Country Status (1)

Country Link
US (5) US7094806B2 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176334A1 (en) * 2000-03-31 2004-09-09 Paratek Pharmaceuticals, Inc. 7-and 9- carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
US20040214801A1 (en) * 2000-07-07 2004-10-28 Paratek Pharmaceuticals, Inc. 9-Substituted minocycline compounds
US20040214800A1 (en) * 2002-10-24 2004-10-28 Levy Stuart B. Methods of using substituted tetracycline compounds to modulate RNA
US20040242548A1 (en) * 2001-04-24 2004-12-02 Michael Draper Substituted tetracycline compounds for the treatment of malaria
US20040266740A1 (en) * 2001-08-02 2004-12-30 Sophie Huss 7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US20050187198A1 (en) * 1999-09-14 2005-08-25 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US20060148765A1 (en) * 2000-05-15 2006-07-06 Paratek Pharmaceuticals, Inc. 7-Substituted fused ring tetracycline compounds
US20060166946A1 (en) * 1999-09-14 2006-07-27 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US20060194773A1 (en) * 2001-07-13 2006-08-31 Paratek Pharmaceuticals, Inc. Tetracyline compounds having target therapeutic activities
US7202235B2 (en) 2000-01-24 2007-04-10 Trustees Of Tufts College Tetracycline compounds for treatment of cryptosporidium parvum related disorders
US20100160656A1 (en) * 2000-06-16 2010-06-24 Nelson Mark L 7-phenyl-substituted tetracycline compounds
US7820641B2 (en) 2002-03-21 2010-10-26 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US7858601B2 (en) 2004-10-25 2010-12-28 Paratek Pharmaceuticals, Inc. 4-substituted tetracyclines and methods of use thereof
US8440646B1 (en) 2006-10-11 2013-05-14 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for treatment of Bacillus anthracis infections
US8466132B2 (en) 2004-10-25 2013-06-18 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US8518912B2 (en) 2007-11-29 2013-08-27 Actelion Pharmaceuticals Ltd. Phosphonic acid derivates and their use as P2Y12 receptor antagonists

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6756365B2 (en) * 1991-11-06 2004-06-29 Trustees Of Tufts College Reducing tetracycline resistance in living cells
US20020123637A1 (en) * 1998-01-23 2002-09-05 Stuart B. Levy Pharmaceutically active compounds and methods of use thereof
US20040224927A1 (en) * 2000-06-16 2004-11-11 Trustees Of Tufts College 7-N-substituted phenyl tetracycline compounds
US20020132798A1 (en) 2000-06-16 2002-09-19 Nelson Mark L. 7-phenyl-substituted tetracycline compounds
KR101083571B1 (en) * 2000-07-07 2011-11-14 파라테크 파마슈티컬스, 인크. 7-substituted tetracycline compounds
US7094806B2 (en) * 2000-07-07 2006-08-22 Trustees Of Tufts College 7, 8 and 9-substituted tetracycline compounds
WO2002072506A2 (en) * 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. 7-pyrollyl tetracycline compounds and methods of use thereof
US7553828B2 (en) 2001-03-13 2009-06-30 Paratek Pharmaceuticals, Inc. 9-aminomethyl substituted minocycline compounds
EP1381372A2 (en) 2001-03-14 2004-01-21 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as synergistic antifungal agents
EP1474380A4 (en) * 2002-01-08 2007-04-18 Paratek Pharm Innc 4-dedimethylamino tetracycline compounds
EP2311451A1 (en) * 2002-03-08 2011-04-20 Paratek Pharmaceuticals, Inc. Amino-methyl substituted tetracycline compounds
KR101089429B1 (en) * 2002-07-12 2011-12-07 파라테크 파마슈티컬스, 인크. 3, 10, AND 12a SUBSTITUTED TETRACYCLINE COMPOUNDS
EA201100956A1 (en) 2003-07-09 2012-01-30 Пэрэтек Фамэсьютикэлс, Инк. SUBSTITUTED TETRACYCLINE COMPOUNDS (OPTIONS), PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATMENT OF TETRACYCLINE-SENSITIVE CONDITION IN SUBJECT
US20060287283A1 (en) * 2003-07-09 2006-12-21 Paratek Pharmaceuticals, Inc. Prodrugs of 9-aminomethyl tetracycline compounds
JP2008530023A (en) * 2005-02-04 2008-08-07 パラテック ファーマシューティカルズ インコーポレイテッド 11a, 12-derivatives of tetracycline compounds
CA2616224A1 (en) * 2005-07-21 2007-02-01 Paratek Pharmaceuticals, Inc. 10-substituted tetracyclines and methods of use thereof
DE602006006016D1 (en) * 2006-01-05 2009-05-14 Cognis Ip Man Gmbh Preparation of epoxy-containing aqueous compositions
CA2652346A1 (en) * 2006-05-15 2007-11-22 Paratek Pharmaceuticals, Inc. Methods of regulating expression of genes or of gene products using substituted tetracycline compounds
ES2463457T3 (en) * 2006-12-21 2014-05-28 Paratek Pharmaceuticals, Inc. Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections
CA2892739A1 (en) 2006-12-21 2008-07-03 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for treatment of inflammatory skin disorders
AU2008239606A1 (en) 2007-04-12 2008-10-23 Paratek Pharmaceuticals, Inc. Methods for treating spinal muscular atrophy using tetracycline compounds
WO2008134048A2 (en) * 2007-04-27 2008-11-06 Paratek Pharmaceuticals, Inc. Methods for synthesizing and purifying aminoalkyl tetracycline compounds
JP2010532759A (en) 2007-07-06 2010-10-14 パラテック ファーマシューティカルズ インコーポレイテッド Method for the synthesis of substituted tetracycline compounds
JP2011513404A (en) * 2008-03-05 2011-04-28 パラテック ファーマシューティカルズ インコーポレイテッド Minocycline compounds and methods of use thereof
US20100022483A1 (en) * 2008-04-14 2010-01-28 Paratek Pharmaceuticals, Inc. Substituted Tetracycline Compounds
EP2307027A4 (en) 2008-07-11 2012-08-15 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
WO2010033939A1 (en) * 2008-09-19 2010-03-25 Paratek Pharmaceuticals, Inc. Tetracycline compounds for the treatment of rheumatoid arthritis and related methods of treatment
MX2019005070A (en) 2016-11-01 2019-09-23 Paratek Pharm Innc 9-aminomethyl minocycline compounds and use thereof in treating community-acquired bacterial pneumonia (cabp).

Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2980684A (en) * 1958-06-02 1961-04-18 Union Carbide Corp Process for dehydrogenating alkyl pyridines
US2990331A (en) * 1956-11-23 1961-06-27 Pfizer & Co C Stable solutions of salts of tetracyclines for parenteral administration
US3007965A (en) * 1959-02-13 1961-11-07 American Cyanamid Co New tetracyclines produced by streptomyces aureofaciens
US3082717A (en) * 1961-03-01 1963-03-26 Manuel F Forte Method of making paper bag
US3165531A (en) * 1962-03-08 1965-01-12 Pfizer & Co C 13-substituted-6-deoxytetracyclines and process utilizing the same
US3226436A (en) * 1963-05-17 1965-12-28 American Cyanamid Co 7-and 9-alkylamino-6-deoxytetracycline
US3338963A (en) * 1960-10-28 1967-08-29 American Cyanamid Co Tetracycline compounds
USRE26263E (en) * 1967-09-05 Process for nixtamalizing whole grain having an inherent moisture content
US3341585A (en) * 1966-05-06 1967-09-12 American Cyanamid Co Substituted 7-and/or 9-amino-6-deoxytetracyclines
USRE26271E (en) * 1967-09-26 Reductive alkylation process
US3345410A (en) * 1966-12-01 1967-10-03 American Cyanamid Co Substituted 7- and/or 9-amino tetracyclines
US3345379A (en) * 1965-02-26 1967-10-03 American Cyanamid Co 7-imidomethyl-6-demethyl-6-deoxytetracyclines
US3360561A (en) * 1967-06-19 1967-12-26 American Cyanamid Co Nitration of tetracyclines
US3373193A (en) * 1963-11-13 1968-03-12 Olin Mathieson Dimeric halophospha (iii)-carboranes and their production
US3397230A (en) * 1966-03-14 1968-08-13 American Cyanamid Co Nitration of tetracyclines
US3403179A (en) * 1967-01-10 1968-09-24 American Cyanamid Co Novel 7-(1, 2-bis-substituted-hydrazino)-tetracyclines and methods of preparing same
US3454697A (en) * 1965-06-08 1969-07-08 American Cyanamid Co Tetracycline antibiotic compositions for oral use
US3483251A (en) * 1967-03-03 1969-12-09 American Cyanamid Co Reductive alkylation process
US3518306A (en) * 1968-02-19 1970-06-30 American Cyanamid Co 7- and/or 9-(n-nitrosoalkylamino)-6-demethyl-6-deoxytetracyclines
US3557280A (en) * 1966-05-31 1971-01-19 Koninklijke Gist Spiritus Stable solutions of oxytetracycline suitable for parenteral and peroral administration and process of preparation
US3579579A (en) * 1968-04-18 1971-05-18 American Cyanamid Co Substituted 7- and/or 9-amino-6-demethyl-6-deoxytetracyclines
US3674859A (en) * 1968-06-28 1972-07-04 Pfizer Aqueous doxycycline compositions
US3849493A (en) * 1966-08-01 1974-11-19 Pfizer D-ring substituted 6-deoxytetracyclines
US3862225A (en) * 1961-08-18 1975-01-21 Pfizer D-ring substituted tetracyclines
US3901942A (en) * 1972-09-18 1975-08-26 Farmaceutici Italia Tetracycline derivatives substituted in the 7 position and process for preparing the same
US3957980A (en) * 1972-10-26 1976-05-18 Pfizer Inc. Doxycycline parenteral compositions
US4018889A (en) * 1976-01-02 1977-04-19 Pfizer Inc. Oxytetracycline compositions
US4024272A (en) * 1974-09-06 1977-05-17 Merck Patent Gesellschaft Mit Beschrankter Haftung Tetracyclic compounds
US4126680A (en) * 1977-04-27 1978-11-21 Pfizer Inc. Tetracycline antibiotic compositions
US5248797A (en) * 1992-08-13 1993-09-28 American Cyanamid Company Method for the production of 9-amino-6-demethyl-6-deoxytetracycline
US5261628A (en) * 1992-02-07 1993-11-16 Abu Garcia Produktion Ab Damping device in an open-face fishing reel of the fixed-spool type
US5284963A (en) * 1992-08-13 1994-02-08 American Cyanamid Company Method of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines
US5326759A (en) * 1991-10-04 1994-07-05 American Cyanamid Company 9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
US5328902A (en) * 1992-08-13 1994-07-12 American Cyanamid Co. 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5371076A (en) * 1993-04-02 1994-12-06 American Cyanamid Company 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
US5386041A (en) * 1992-08-13 1995-01-31 American Cyanamid Company 7-(substituted)-8-(substituted)-9-[(substituted glycyl) amido]-6-demethyl-6-deoxytetracyclines
US5430162A (en) * 1992-08-13 1995-07-04 American Cyanamid Company 7-(substituted)-8-(substituted)-9-substituted amino)-6-demethyl-6-deoxytetracyclines
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5532227A (en) * 1992-11-17 1996-07-02 The Research Foundation Of State University Of New York Tetracyclines including non-antimicrobial chemically-modified tetracyclines inhibit excessive glycosylation of different types of collagen and other proteins during diabetes
US5675030A (en) * 1994-11-16 1997-10-07 American Cyanamid Company Method for selective extracting a 7-(hydrogen or substituted amino)-9- (substituted glycyl) amido!-6-demethyl-6-deoxytetracycline compound
US5789395A (en) * 1996-08-30 1998-08-04 The Research Foundation Of State University Of New York Method of using tetracycline compounds for inhibition of endogenous nitric oxide production
US5834450A (en) * 1994-02-17 1998-11-10 Pfizer Inc. 9- (substituted amino) -alpha-6-deoxy-5-oxy tetracycline derivatives, their preparation and their use as antibiotics
US6617318B1 (en) * 1999-09-14 2003-09-09 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US6683068B2 (en) * 2001-03-13 2004-01-27 Paratek Pharmaceuticals, Inc. 7, 9-substituted tetracycline compounds
US6816634B2 (en) * 2000-11-30 2004-11-09 Dainippon Screen Mfg. Co., Ltd. Image recorder
US6818635B2 (en) * 2000-07-07 2004-11-16 Paratek Pharmaceuticals, Inc. 7-substituted tetracycline compounds
US20040242648A1 (en) * 2002-10-07 2004-12-02 Artesian Therapeutics, Inc. Compounds having simultaneous ability to block L-type calcium channels and to inhibit phosphodiesterase type 3 activity
US6841546B2 (en) * 2001-03-14 2005-01-11 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as antifungal agents
US6846939B2 (en) * 2000-07-07 2005-01-25 Paratek Pharmaceuticals, Inc. 9-substituted minocycline compounds

Family Cites Families (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2980584A (en) 1957-10-29 1961-04-18 Pfizer & Co C Parenteral magnesium oxytetracycline acetic or lactic acid carboxamide vehicle preparation
US3062717A (en) 1958-12-11 1962-11-06 Pfizer & Co C Intramuscular calcium tetracycline acetic or lactic acid carboxamide vehicle preparation
DE1249134B (en) 1959-05-09 1967-08-31
US3338983A (en) 1964-01-24 1967-08-29 Exxon Research Engineering Co Purification of alkyl aryl hydrocarbons
US3609188A (en) 1964-10-29 1971-09-28 American Cyanamid Co 4-dedimethylamino-4-substituted-amino-6-demethyltetracyclines
DE1542790A1 (en) 1965-09-27 1970-05-06 Bayer Ag Anti-phytopathogenic bacteria
US3388162A (en) 1966-03-14 1968-06-11 American Cyanamid Co 7-and/or 9-nitro or amino tetracyclines
US3579578A (en) 1966-07-08 1971-05-18 Givaudan Corp 3,4-dihalo-3' and 4'-lower alkylcarbanilides
JPS5119757A (en) 1974-06-25 1976-02-17 Farmaceutici Italia ARUKIRUTETORASAIKURIN JUDOTAINOSEIZOHO
US5064821A (en) 1982-11-18 1991-11-12 Trustees Of Tufts College Method and compositions for overcoming tetracycline resistance within living cells
ATE211128T1 (en) 1991-10-04 2002-01-15 American Cyanamid Co 7-SUBSTITUTED-9-SUBSTITUTED AMINO-6-DEMETHYL-6-DEOXY-TETRACYCLINE
US5326459A (en) * 1992-11-12 1994-07-05 Envirex Inc. Wastewater treatment apparatus
US5363765A (en) 1993-03-12 1994-11-15 Asahi Kasei Kogyo Kabushiki Kaisha Electronic delay circuit for firing ignition element
US5567693A (en) 1994-12-13 1996-10-22 American Cyanamid Company Method for inhibiting angiogenesis, proliferation of endothelial or tumor cells and tumor growth
WO1996034852A1 (en) 1995-05-03 1996-11-07 Pfizer, Inc. Novel tetracycline derivatives
DE19728476A1 (en) * 1997-07-03 1999-01-07 Siemens Ag Programming device
US20020123637A1 (en) 1998-01-23 2002-09-05 Stuart B. Levy Pharmaceutically active compounds and methods of use thereof
US6946453B2 (en) 1998-11-18 2005-09-20 Collagenex Pharmaceuticals, Inc. 4-dedimethylaminotracycline derivatives
US6506740B1 (en) 1998-11-18 2003-01-14 Robert A. Ashley 4-dedimethylaminotetracycline derivatives
US6849615B2 (en) 1999-09-14 2005-02-01 Paratek Pharmaceuticals, Inc. 13-substituted methacycline compounds
US6500812B2 (en) 1999-09-14 2002-12-31 Paratek Pharmaceuticals, Inc. 13-substituted methacycline compounds
CA2326557C (en) * 1999-11-18 2006-03-14 Kuraray Co., Ltd. Saponified, alkoxyl group-containing ethylene-vinyl acetate copolymer, and its processed products
EP1263442A1 (en) 2000-01-24 2002-12-11 Trustees Of Tufts College TETRACYCLINE COMPOUNDS FOR TREATMENT OF i CRYPTOSPORIDIUM PARVUM /i RELATED DISORDERS
BR0109725A (en) 2000-03-31 2003-02-04 Tufts College Substituted tetracycline compound, method for treating a tetracycline-responsive state in a mammal, pharmaceutical composition, method for synthesizing a 7- or 9-substituted tetracycline compound, and reactive intermediate
ATE264295T1 (en) 2000-05-15 2004-04-15 Paratek Pharm Innc 7-SUBSTITUTED CONDENSED RING TETRACYCLINE COMPOUNDS
US20020128237A1 (en) 2000-06-16 2002-09-12 Nelson Mark L. 7-N-substituted phenyl tetracycline compounds
AU2001268475A1 (en) 2000-06-16 2002-01-02 Trustees Of Tufts College 7-phenyl-substituted tetracycline compounds
US20020132798A1 (en) 2000-06-16 2002-09-19 Nelson Mark L. 7-phenyl-substituted tetracycline compounds
CA2415086A1 (en) 2000-07-07 2002-01-17 Trustees Of Tufts College 7,8 and 9-substituted tetracycline compounds
US20050143353A1 (en) 2000-07-07 2005-06-30 Paratek Pharmaceuticals, Inc. 13-Substituted methacycline compounds
US7094806B2 (en) 2000-07-07 2006-08-22 Trustees Of Tufts College 7, 8 and 9-substituted tetracycline compounds
EP1241160A1 (en) 2001-03-13 2002-09-18 Glaxo Group Limited Tetracycline derivatives and their use as antibiotic agents
WO2002072506A2 (en) 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. 7-pyrollyl tetracycline compounds and methods of use thereof
US7553828B2 (en) 2001-03-13 2009-06-30 Paratek Pharmaceuticals, Inc. 9-aminomethyl substituted minocycline compounds
EP1381372A2 (en) 2001-03-14 2004-01-21 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as synergistic antifungal agents
US8088820B2 (en) 2001-04-24 2012-01-03 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for the treatment of malaria
EP1399414B1 (en) 2001-04-24 2010-01-13 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for the treatment of malaria
EP2301915A1 (en) 2001-07-13 2011-03-30 Paratek Pharmaceuticals, Inc. 7-(diethylamino)methyl substituted tetracycline having target therapeutic activities
US20060194773A1 (en) 2001-07-13 2006-08-31 Paratek Pharmaceuticals, Inc. Tetracyline compounds having target therapeutic activities
AU2002365120A1 (en) 2001-08-02 2003-07-15 Paratek Pharmaceuticals, Inc. Medicaments
CN1961885A (en) 2001-10-05 2007-05-16 泰特拉吉尼克斯医药公司 Tetracycline derivatives and methods of use thereof
US20030114535A1 (en) 2001-12-14 2003-06-19 Jame Fine Chemicals, Inc. Dextrochlorpheniramine tannate
EP1474380A4 (en) 2002-01-08 2007-04-18 Paratek Pharm Innc 4-dedimethylamino tetracycline compounds
EP2311451A1 (en) 2002-03-08 2011-04-20 Paratek Pharmaceuticals, Inc. Amino-methyl substituted tetracycline compounds
EP1503981A4 (en) 2002-03-21 2007-08-15 Paratek Pharm Innc Substituted tetracycline compounds
KR101089429B1 (en) 2002-07-12 2011-12-07 파라테크 파마슈티컬스, 인크. 3, 10, AND 12a SUBSTITUTED TETRACYCLINE COMPOUNDS
US6760673B2 (en) 2002-07-31 2004-07-06 Agilent Technologies, Inc. Method and apparatus for waveform measurement instrument
WO2004038000A2 (en) 2002-10-24 2004-05-06 Paratek Pharmaceuticals, Inc. Methods of using substituted tetracycline compounds to modulate rna
WO2005009944A1 (en) 2003-07-09 2005-02-03 Paratek Pharmaceuticals, Inc. Prodrugs of 9-aminomethyl tetracycline compounds
EA201100956A1 (en) 2003-07-09 2012-01-30 Пэрэтек Фамэсьютикэлс, Инк. SUBSTITUTED TETRACYCLINE COMPOUNDS (OPTIONS), PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATMENT OF TETRACYCLINE-SENSITIVE CONDITION IN SUBJECT
EP1716101A1 (en) 2004-01-15 2006-11-02 Paratek Pharmaceuticals, Inc. Aromatic a-ring derivatives of tetracycline compounds
WO2005082860A1 (en) 2004-02-27 2005-09-09 National Research Council Of Canada Tetracyclines and their use as calpain inhibitors
GB0410741D0 (en) * 2004-05-14 2004-06-16 Inqbator Ltd Ball game practice device
HUE030212T2 (en) 2004-05-21 2017-04-28 Harvard College Synthesis of tetracyclines and analogues thereof
EP2305637A3 (en) 2004-10-25 2011-09-21 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
EP2301916A3 (en) 2004-10-25 2011-09-28 Paratek Pharmaceuticals, Inc. 4-aminotetracyclines and methods of use thereof
JP2008530023A (en) 2005-02-04 2008-08-07 パラテック ファーマシューティカルズ インコーポレイテッド 11a, 12-derivatives of tetracycline compounds
CA2616224A1 (en) 2005-07-21 2007-02-01 Paratek Pharmaceuticals, Inc. 10-substituted tetracyclines and methods of use thereof
EP1991236A2 (en) 2006-01-24 2008-11-19 Paratek Pharmaceuticals, Inc. Methods of increasing oral bioavailability of tetracyclines
CA2652346A1 (en) 2006-05-15 2007-11-22 Paratek Pharmaceuticals, Inc. Methods of regulating expression of genes or of gene products using substituted tetracycline compounds
CA2892739A1 (en) 2006-12-21 2008-07-03 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for treatment of inflammatory skin disorders
AU2008239606A1 (en) 2007-04-12 2008-10-23 Paratek Pharmaceuticals, Inc. Methods for treating spinal muscular atrophy using tetracycline compounds
WO2008134048A2 (en) 2007-04-27 2008-11-06 Paratek Pharmaceuticals, Inc. Methods for synthesizing and purifying aminoalkyl tetracycline compounds
JP2010532759A (en) 2007-07-06 2010-10-14 パラテック ファーマシューティカルズ インコーポレイテッド Method for the synthesis of substituted tetracycline compounds

Patent Citations (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE26263E (en) * 1967-09-05 Process for nixtamalizing whole grain having an inherent moisture content
USRE26271E (en) * 1967-09-26 Reductive alkylation process
US2990331A (en) * 1956-11-23 1961-06-27 Pfizer & Co C Stable solutions of salts of tetracyclines for parenteral administration
US2980684A (en) * 1958-06-02 1961-04-18 Union Carbide Corp Process for dehydrogenating alkyl pyridines
US3007965A (en) * 1959-02-13 1961-11-07 American Cyanamid Co New tetracyclines produced by streptomyces aureofaciens
US3338963A (en) * 1960-10-28 1967-08-29 American Cyanamid Co Tetracycline compounds
US3082717A (en) * 1961-03-01 1963-03-26 Manuel F Forte Method of making paper bag
US3862225A (en) * 1961-08-18 1975-01-21 Pfizer D-ring substituted tetracyclines
US3165531A (en) * 1962-03-08 1965-01-12 Pfizer & Co C 13-substituted-6-deoxytetracyclines and process utilizing the same
US3226436A (en) * 1963-05-17 1965-12-28 American Cyanamid Co 7-and 9-alkylamino-6-deoxytetracycline
US3373193A (en) * 1963-11-13 1968-03-12 Olin Mathieson Dimeric halophospha (iii)-carboranes and their production
US3345379A (en) * 1965-02-26 1967-10-03 American Cyanamid Co 7-imidomethyl-6-demethyl-6-deoxytetracyclines
US3454697A (en) * 1965-06-08 1969-07-08 American Cyanamid Co Tetracycline antibiotic compositions for oral use
US3397230A (en) * 1966-03-14 1968-08-13 American Cyanamid Co Nitration of tetracyclines
US3341585A (en) * 1966-05-06 1967-09-12 American Cyanamid Co Substituted 7-and/or 9-amino-6-deoxytetracyclines
US3557280A (en) * 1966-05-31 1971-01-19 Koninklijke Gist Spiritus Stable solutions of oxytetracycline suitable for parenteral and peroral administration and process of preparation
US3849493A (en) * 1966-08-01 1974-11-19 Pfizer D-ring substituted 6-deoxytetracyclines
US3345410A (en) * 1966-12-01 1967-10-03 American Cyanamid Co Substituted 7- and/or 9-amino tetracyclines
US3403179A (en) * 1967-01-10 1968-09-24 American Cyanamid Co Novel 7-(1, 2-bis-substituted-hydrazino)-tetracyclines and methods of preparing same
US3483251A (en) * 1967-03-03 1969-12-09 American Cyanamid Co Reductive alkylation process
US3360561A (en) * 1967-06-19 1967-12-26 American Cyanamid Co Nitration of tetracyclines
US3518306A (en) * 1968-02-19 1970-06-30 American Cyanamid Co 7- and/or 9-(n-nitrosoalkylamino)-6-demethyl-6-deoxytetracyclines
US3579579A (en) * 1968-04-18 1971-05-18 American Cyanamid Co Substituted 7- and/or 9-amino-6-demethyl-6-deoxytetracyclines
US3674859A (en) * 1968-06-28 1972-07-04 Pfizer Aqueous doxycycline compositions
US3901942A (en) * 1972-09-18 1975-08-26 Farmaceutici Italia Tetracycline derivatives substituted in the 7 position and process for preparing the same
US3957980A (en) * 1972-10-26 1976-05-18 Pfizer Inc. Doxycycline parenteral compositions
US4024272A (en) * 1974-09-06 1977-05-17 Merck Patent Gesellschaft Mit Beschrankter Haftung Tetracyclic compounds
US4018889A (en) * 1976-01-02 1977-04-19 Pfizer Inc. Oxytetracycline compositions
US4126680A (en) * 1977-04-27 1978-11-21 Pfizer Inc. Tetracycline antibiotic compositions
US5530117A (en) * 1991-10-04 1996-06-25 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5401863A (en) * 1991-10-04 1995-03-28 American Cyanamid Company 9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
US5326759A (en) * 1991-10-04 1994-07-05 American Cyanamid Company 9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
US5529990A (en) * 1991-10-04 1996-06-25 American Cyanamid Company Method for treating bacterial infection with novel 7-substituted-9-substituted amino 6-demethyl-6-deoxytetracyclines
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5261628A (en) * 1992-02-07 1993-11-16 Abu Garcia Produktion Ab Damping device in an open-face fishing reel of the fixed-spool type
US5284963A (en) * 1992-08-13 1994-02-08 American Cyanamid Company Method of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines
US5248797A (en) * 1992-08-13 1993-09-28 American Cyanamid Company Method for the production of 9-amino-6-demethyl-6-deoxytetracycline
US5380888A (en) * 1992-08-13 1995-01-10 American Cyanamid Company 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5401729A (en) * 1992-08-13 1995-03-28 American Cyanamid Company 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5420272A (en) * 1992-08-13 1995-05-30 American Cyanamid Company 7-(substituted)-8-(substituted)-9-](substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5430162A (en) * 1992-08-13 1995-07-04 American Cyanamid Company 7-(substituted)-8-(substituted)-9-substituted amino)-6-demethyl-6-deoxytetracyclines
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5457096A (en) * 1992-08-13 1995-10-10 American Cyanamid Company 7-(substituted)-8-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5466684A (en) * 1992-08-13 1995-11-14 American Cyanamid Company 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5495030A (en) * 1992-08-13 1996-02-27 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5495031A (en) * 1992-08-13 1996-02-27 American Cyanamid Company Process for the production of 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5886175A (en) * 1992-08-13 1999-03-23 American Cyanamid Company 7-(substituted)-8-(substituted)-9-(substitued amino)-6-demethyl-6-deoxytetracyclines
US5495018A (en) * 1992-08-13 1996-02-27 American Cyanamid Company 7-(substituted-9-(substituted amino)-6-demethyl-6-deoxytetracyclines
US5512553A (en) * 1992-08-13 1996-04-30 American Cyanamid Company 7-(substituted)-8-(substituted)-9-(substituted amino)-6-demethyl-6-deoxytetracyclines
US5328902A (en) * 1992-08-13 1994-07-12 American Cyanamid Co. 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5386041A (en) * 1992-08-13 1995-01-31 American Cyanamid Company 7-(substituted)-8-(substituted)-9-[(substituted glycyl) amido]-6-demethyl-6-deoxytetracyclines
US5567692A (en) * 1992-08-13 1996-10-22 American Cyanamid Company 9-[(substituted glycyl) amido)]-6-demethyl-6-deoxytetracyclines
US5532227A (en) * 1992-11-17 1996-07-02 The Research Foundation Of State University Of New York Tetracyclines including non-antimicrobial chemically-modified tetracyclines inhibit excessive glycosylation of different types of collagen and other proteins during diabetes
US5639742A (en) * 1993-04-02 1997-06-17 Lee; Ving Jick 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
US5371076A (en) * 1993-04-02 1994-12-06 American Cyanamid Company 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
US5834450A (en) * 1994-02-17 1998-11-10 Pfizer Inc. 9- (substituted amino) -alpha-6-deoxy-5-oxy tetracycline derivatives, their preparation and their use as antibiotics
US5675030A (en) * 1994-11-16 1997-10-07 American Cyanamid Company Method for selective extracting a 7-(hydrogen or substituted amino)-9- (substituted glycyl) amido!-6-demethyl-6-deoxytetracycline compound
US5789395A (en) * 1996-08-30 1998-08-04 The Research Foundation Of State University Of New York Method of using tetracycline compounds for inhibition of endogenous nitric oxide production
US6617318B1 (en) * 1999-09-14 2003-09-09 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US6818635B2 (en) * 2000-07-07 2004-11-16 Paratek Pharmaceuticals, Inc. 7-substituted tetracycline compounds
US6846939B2 (en) * 2000-07-07 2005-01-25 Paratek Pharmaceuticals, Inc. 9-substituted minocycline compounds
US6816634B2 (en) * 2000-11-30 2004-11-09 Dainippon Screen Mfg. Co., Ltd. Image recorder
US6683068B2 (en) * 2001-03-13 2004-01-27 Paratek Pharmaceuticals, Inc. 7, 9-substituted tetracycline compounds
US6841546B2 (en) * 2001-03-14 2005-01-11 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds as antifungal agents
US20040242648A1 (en) * 2002-10-07 2004-12-02 Artesian Therapeutics, Inc. Compounds having simultaneous ability to block L-type calcium channels and to inhibit phosphodiesterase type 3 activity

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187198A1 (en) * 1999-09-14 2005-08-25 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US8106225B2 (en) 1999-09-14 2012-01-31 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US7696187B2 (en) 1999-09-14 2010-04-13 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US20060166946A1 (en) * 1999-09-14 2006-07-27 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US7202235B2 (en) 2000-01-24 2007-04-10 Trustees Of Tufts College Tetracycline compounds for treatment of cryptosporidium parvum related disorders
US7858600B2 (en) 2000-03-31 2010-12-28 Paratek Pharmaceuticals, Inc. 7- and 9- carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
US20040176334A1 (en) * 2000-03-31 2004-09-09 Paratek Pharmaceuticals, Inc. 7-and 9- carbamate, urea, thiourea, thiocarbamate, and heteroaryl-amino substituted tetracycline compounds
US20110092467A1 (en) * 2000-03-31 2011-04-21 Paratek Pharmaceuticals, Inc. 7-And 9-Carbamate, Urea, Thiourea, Thiocarbamate, And Heteroaryl-Amino Substituted Tetracycline Compounds
US7893282B2 (en) 2000-05-15 2011-02-22 Paratek Pharmaceuticals, Inc. 7-substituted fused ring tetracycline compounds
US20060148765A1 (en) * 2000-05-15 2006-07-06 Paratek Pharmaceuticals, Inc. 7-Substituted fused ring tetracycline compounds
US8288570B2 (en) 2000-05-15 2012-10-16 Paratek Pharmaceuticals, Inc. 7-iodo tetracyclines and related methods
US20080300424A1 (en) * 2000-05-15 2008-12-04 Paratek Pharmaceuticals, Inc. 7-substituted fused ring tetracycline compounds
US7612053B2 (en) 2000-05-15 2009-11-03 Paratek Pharmaceuticals, Inc. 7-Substituted fused ring tetracycline compounds
US20110207951A1 (en) * 2000-05-15 2011-08-25 Paratek Pharmaceuticals, Inc. 7-Iodo Tetracyclines and Related Methods
US20100160656A1 (en) * 2000-06-16 2010-06-24 Nelson Mark L 7-phenyl-substituted tetracycline compounds
US8119622B2 (en) 2000-06-16 2012-02-21 Trustees Of Tufts College 7-phenyl-substituted tetracycline compounds
US20040214801A1 (en) * 2000-07-07 2004-10-28 Paratek Pharmaceuticals, Inc. 9-Substituted minocycline compounds
US9090541B2 (en) 2000-07-07 2015-07-28 Paratek Pharmaceuticals, Inc. 9-substituted minocycline compounds
US8258120B2 (en) 2000-07-07 2012-09-04 Paratek Pharmaceuticals, Inc. 9-substituted minocycline compounds
US8048867B2 (en) 2000-07-07 2011-11-01 Trustees Of Tufts College 9-substituted minocycline compounds
US20040242548A1 (en) * 2001-04-24 2004-12-02 Michael Draper Substituted tetracycline compounds for the treatment of malaria
US8088820B2 (en) 2001-04-24 2012-01-03 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for the treatment of malaria
US20060194773A1 (en) * 2001-07-13 2006-08-31 Paratek Pharmaceuticals, Inc. Tetracyline compounds having target therapeutic activities
US8211937B2 (en) 2001-08-02 2012-07-03 Paratek Pharmaceuticals, Inc. 7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US7323492B2 (en) 2001-08-02 2008-01-29 Paratek Pharmaceuticals, Inc. 7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US20040266740A1 (en) * 2001-08-02 2004-12-30 Sophie Huss 7-pyrollyl 9-aminoacyl tetracycline compounds and methods of use thereof
US7820641B2 (en) 2002-03-21 2010-10-26 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US8173624B2 (en) 2002-10-24 2012-05-08 Paratek Pharmaceuticals, Inc. Methods of using substituted tetracycline compounds to modulate RNA
US20040214800A1 (en) * 2002-10-24 2004-10-28 Levy Stuart B. Methods of using substituted tetracycline compounds to modulate RNA
US9562003B2 (en) 2002-10-24 2017-02-07 Paratek Pharmaceuticals, Inc. Methods of using substituted tetracycline compounds to modulate RNA
US20110077225A1 (en) * 2004-10-25 2011-03-31 Paratek Pharmaceuticals, Inc. 4-Substituted Tetracyclines and Methods of Use Thereof
US7858601B2 (en) 2004-10-25 2010-12-28 Paratek Pharmaceuticals, Inc. 4-substituted tetracyclines and methods of use thereof
US8466132B2 (en) 2004-10-25 2013-06-18 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US8440646B1 (en) 2006-10-11 2013-05-14 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds for treatment of Bacillus anthracis infections
US8518912B2 (en) 2007-11-29 2013-08-27 Actelion Pharmaceuticals Ltd. Phosphonic acid derivates and their use as P2Y12 receptor antagonists

Also Published As

Publication number Publication date
US7094806B2 (en) 2006-08-22
US7875649B2 (en) 2011-01-25
US8252777B2 (en) 2012-08-28
US7696188B2 (en) 2010-04-13
US7361674B2 (en) 2008-04-22
US20110118215A1 (en) 2011-05-19
US20080167273A1 (en) 2008-07-10
US20060229282A1 (en) 2006-10-12
US20100160265A1 (en) 2010-06-24

Similar Documents

Publication Publication Date Title
US6624168B2 (en) 7,8 and 9-substituted tetracycline compounds
US7361674B2 (en) 7, 8 and 9-substituted tetracycline compounds
US8012951B2 (en) 7-N-substituted phenyl tetracycline compounds
US8288570B2 (en) 7-iodo tetracyclines and related methods
US8119622B2 (en) 7-phenyl-substituted tetracycline compounds
US20020128237A1 (en) 7-N-substituted phenyl tetracycline compounds
WO2001098260A1 (en) 7-n-substituted phenyl tetracycline compounds
WO2002012170A1 (en) 8-substituted tetracycline compounds
EP1426369A1 (en) 7-Substituted fused ring tetracycline compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: TUFTS COLLEGE, TRUSTEES OF, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NELSON, MARK L.;KOZA, DARRELL J.;RENNIE, GLEN;REEL/FRAME:015872/0931;SIGNING DATES FROM 20041202 TO 20050308

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: MINTZ LEVIN COHN FERRIS GLOVSKY AND POPEO PC, MASS

Free format text: NOTICE;ASSIGNOR:PARATEK PHARMACEUTICALS, INC.;REEL/FRAME:029940/0106

Effective date: 20130308

AS Assignment

Owner name: HBM HEALTHCARE INVESTMENTS (CAYMAN) LTD., AS COLLA

Free format text: SECURITY INTEREST;ASSIGNOR:PARATEK PHARMACEUTICALS, INC.;REEL/FRAME:032448/0001

Effective date: 20140307

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Expired due to failure to pay maintenance fee

Effective date: 20140822

AS Assignment

Owner name: PARATEK PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:HBM HEALTHCARE INVESTMENTS (CAYMAN) LTD., AS COLLATERAL AGENT;REEL/FRAME:034113/0910

Effective date: 20141031

AS Assignment

Owner name: PARATEK PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: TERMINATION OF LIEN ON PATENTS;ASSIGNOR:MINTZ LEVIN COHN FERRIS GLOVSKY AND POPEO PC;REEL/FRAME:034700/0377

Effective date: 20141222